Management of Anovulatory Infertility Associated With Polycystic Ovary Syndrome: Tamoxifen Citrate an Effective Alternative Compound to Clomiphene Citrate

Key words: TAMOXIFEN CITRATE, CLOMIPHENE CITRATE, POLYCYSTIC OVARY SYNDROME, OVULATION INDUCTION

ABSTRACT

Clomiphene citrate (CC) is widely used as first-line treatment for ovulation induction in anovulatory women with polycystic ovary syndrome (PCOS). Tamoxifen citrate (TMX), another non-steroidal selective estrogen receptor modulator, may also be effective on the resumption of ovulation in these women. The aim of this controlled observational study was to compare the efficacy and safety of ovulation induction with TMX versus CC in anovulatory infertile women with PCOS. A total of 102 consecutive women (mean age SD: 31 3.6 years; range: 26-38) with PCOS were studied. Following a spontaneous or progesterone-induced withdrawal bleed, women received either 50 mg daily of CC (days 2-6) or 20 mg daily of TMX (days 2- 5). In case ovulation failed to occur, the dose was sequentially increased to 100 mg daily of CC and 40 mg daily of TMX, respectively. Serum progesterone levels were measured on cycle day 21 to monitor the ovulation pattern. The overall ovulation rate was significantly higher in women who received TMX compared with those who received CC (61/98, 62.2% vs. 60/127, 47.2%, p = 0.03). Although not statistically significant, the pregnancy rate per ovnlatory cycle was higher in the TMX group compared to the CC group (14/61, 22. 9% vs. 11/60, 18.3%, respectively). All pregnancies were single and there were no side-effects in either group of treatment. Collectively, these data demonstrate that TMX is a safe and effective agent, and a suitable alternative to CC for anovulatory infertility in women with PCOS.

INTRODUCTION

Polycystic ovary syndrome (PCOS), also known as Stem-Leventhal syndrome, is a very heterogeneous endocrine disorder affecting women of reproductive age1. It is normally diagnosed on the basis of typical ovarian morphology and clinical and biochemical indices2,3. A large body of evidence has shown that the abnormal circulating hormones correlate positively with some morphological features4 and with adverse fertility and pregnancy outcome5.

Ovulation induction and pregnancy outcome remain a major challenge in infertile women with PCOS. Amongst several agents commercially available, clomiphene citrate (CC) continues to be the first line of treatment for anovulatory infertility in these women. While the use of this compound is relatively well known in terms of ovulation rate, safety and side-effects, the pregnancy outcome remains much lower than expected6. Another selective estrogen receptor modulator (SERM), tamoxifen citrate (TMX), has been recently reported to be equally effective in pregnancy outcome and for inducing ovulation in an unselected population of anovulatory women with infertility7. A comprehensive pharmacological review of SERMs has highlighted the estrogen agonist and estrogen antagonist effects of these compounds and their tissue specificity8.

The objective of the present observational study was to investigate the efficacy and safety of ovulation induction with CC and TMX in a large population of anovulatory infertile women with PCOS.

MATERIALS AND METHODS

A total of 102 consecutive anovulatory infertile women (mean age SD: 31 + 3.6 years; range: 26-38) with PCOS referred to the infertility clinic were studied. A complete infertility work-up was conducted on all women and their partners to investigate further the cause of infertility. Inclusion criteria were as follows: age below 40 years, bilateral tubal patency as confirmed either by hysterosalpin-go-contrast sonography (HyCoSy) or by the Lap&Dye test, biochemical indices and ultrasonographic features of PCOS1,2,4,5, absence of any other endocnnopathy and semen parameters within the normal range (World Health Organization (WHO) criteria, 1992)9.

Following a spontaneous or progesterone-induced (10 mg oral medroxyprogesterone acetate, Provera; Pharmacia and Upjohn, Bucks, UK) withdrawal bleed, all women received either CC 50 mg daily (Clomid; Aventis Phanna, Kent, UK) during cycle days 2-6 or TMX 20 mg daily (Nolvadex; AstraZeneca Ltd, Herts, UK) during cycle days 2- 5. The method of treatment allocation was casual and no specific criteria were required to enter one or the other protocol. In case ovulation failed to occur with the initial dose of either compound, then the dose was sequentially increased to 100 mg of CC during cycle days 2-6 or 40 mg of TMX during cycle days 2-5. All women were treated for a period no longer than six consecutive cycles. Before being prescribed either CC or TMX, women were made aware of the increased nsk of multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) following ovulation induction with these agents. Also, all of them were invited to report any side-efrect experienced during and/or after treatment. Institutional Review Board (IRB) approval was not required, because patients were recommended treatments that were in keeping with the usual departmental clinical practice.

All women were instructed to have a blood test for progesterone measurement (competitive immunoassay, Chemiluminescence; Bayer, Berkshire, UK) on day 21 of the menstrual cycle. Serum progesterone levels of ≥ 30 nmol/l were considered to be presumptive evidence of ovulation. Pregnancy was confirmed by detection of urinary human chorionic gonadotropin (hCG; monoclonal antibody- based immunoassay; Unipath Ltd., Bedford, Bedfordshire, UK) and subsequent ultrasonography at X-12 weeks’ gestation.

Data were analyzed by two-way analysis of variance (ANOVA) and Fisher’s exact test. The difference between the two groups was estimated with the 95% confidence interval (CI). The software Statistics Package for Social Science 10.0 for Windows (SPSS Inc.; Ghicago, IL, USA) was used for statistical calculations. A value of p < 0.05 was assumed to be statistically significant.

RESULTS

Fifty-nine women received CC and 43 received TMX. There were no significant differences between the study groups. Demographic characteristics of the study population (n= 102) are reported in Table 1. No side-effects, symptoms or signs of ovarian hyperstimulation were reported in either group. The total number of treatment cycles with CC and TMX was 127 and 98, respectively.

Table 1 Demographic characteristics of the study population (n = 102)

The overall rate of ovulation in the CC group was 60 out of 127 cycles (47.2%) and in the TMX group it was 61 out of 98 cycles (62.2%) (OR 0.54; 95% CI 0.31-0.92; p = 0.03). Table 2 shows data concerning ovulation rate per cycle in women receiving cither low- dose or high-dose treatment for ovulation induction.

At the end of the 6-month study period, the pregnancies recorded were 11 in the CC group and 14 in the TMX group. All the pregnancies were normal and single in both groups of treatment. The pregnancy rate per ovulatory cycle in the CC group and TMX group is reported in Table 3.

DISCUSSION

PCOS is the most common cause of anovulatory infertility amongst women who desire to conceive. Although administration of exogenous agents represents the standard of care, this approach carries considerable costs, time and risks. CC is one of the most widely used drugs for ovulation induction. However, since a significant proportion of women with PCOS fail to ovulate on standard dosage of CC, high doses, prolonged treatment and multiple courses are often needed to achieve ovulation.

The present observational study showed that TMX had a better efficacy than CC, and a similar safety, in a selected population of anovulatory infertile women with PCOS. Collectively, these results are in contrast with those of earlier studies7,10 which demonstrated that TMX had similar effectiveness to CC for ovulation induction in infertile women. These discrepancies may well be explained by differences in protocol design and study population. In this study, we considered a selected population of anovulatory infertile women with biochemical indices and sonographic features of PCOS1,2,4,5, and all women were given the same compound for the whole period of treatment. In contrast, while Messinis and Nillius10 administered TMX and CC in an alternate way to all women, Boostanfar and co- workers7 analyzed a general population of anovulatory women with unexplained infertility.

Table 2 Ovulation rate per cycle in the clomiphe citrate (CC) group and the tamoxifen (TMX) group

Although it was not the objective of this study to investigate the optimal dosage of treatment, the ovulatory rate per cycle was significantly higher with low-dose TMX compared to low-dose CC. Conversely, no significant difference was found when both compounds were administered at high closes. Whether these effects are due to different pharmacokinetic and pharmacodynamic properties remains to be confirmed8. However, it seems plausible that lower doses of TMX, compared to CC, are necessary to produce antiestrogenic effects in the hypothalamus.

Concerning the pregnancy rate per ovulatory cycle, there was no significant difference between the two groups. Nevertheless, in agreement with other authors7, the present data show a trend towards a slightly higher pregnancy rate in women treated with TMX with respect to those treated with CC. Adverse events associated with CC such as cervical mucus abnormalities and luteal phase deficiency may w\ell address this issue11. More recently, Wu12 reported a lower miscarriage rate in women with luteal phase dysfunction following TMX administration as compared with CC administration. Therefore, the estrogenic stimulatory effects of TMX on the lower genital tract and endometrium may be beneficial.

Table 3 Pregnancy rate in the study population following treatment with either clomiphene citrate (CC) or tamoxifen citrate (TMX)

In agreement with previous reports7,13,14, the ovulation induction protocol with TMX appears to be as safe as that with CC. There were no cases of OHSS and all women completed the study protocol without experiencing any side-effects such as headache, nausea, vomiting, visual disturbances, abdominal or pelvic pain or abnormal vaginal bleeding. Moreover, there were no multiple pregnancies or fetal-maternal problems in either treatment group.

In conclusion, analysis of this large cohort of anovulatory infertile women with PCOS demonstrates that TMX is an effective and suitable alternative agent to CC for ovulation induction. Although the clinical significance is likely to be small, particularly as TMX has no licence for ovulation induction, the validation of this new treatment modality for ovulation induction should encourage further studies in gynecological endocrinology to investigate the long-term prognosis. In the current climate of evidence-based practice, the case for TMX as safe management for ovulation induction in women with PCOS appears to be clear. Prospective randomized studies with adequate statistical power are needed to understand whether TMX might play a role in CC-resistant women with PCOS and also to assess its correlation with endometrial thickness during the implantation window.

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L. G. Nardo

Department of Reproductive Medicine, St Mary’s Hospital, Manchester, UK

Correspondence: Dr L. G. Nardo, Department of Reproductive Medicine, St Mary’s Hospital, Whitworth Park, Manchester, M13 0JH, UK Tel: +44(0) 161 276 6371 Fax: +44(0) 161 224 0957 E-mail: Luciano.Nardo@CMMC.NHS.UK

Copyright CRC Press Nov 2004